JPS58135807A - Preparation of drug having enteric coating - Google Patents

Abstract

PURPOSE:To prepare the titled drug without using an organic solvent, by using a solution obtained by dissolving an enteric cellulose derivative in an alkaline aqueous solution, and adding a carboxylic acid to the solution. CONSTITUTION:An enteric cellulose derivative such as hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose, etc. is dissolved in an alkaline aqueous solution (the alkali is e.g. alkali metal hydroxide or carbonate, or ammonia), a carboxylic acid is added to the solution in an amount of >=50%, preferably >=60% equivalent of the alkali, and the resultant solution is applied to a solid drug such as tablet, capsule, etc. by conventional method. To prevent the precipitation of large gelatinous lumps, the carboxylic acid is diluted with water (usually to a concentration of <=5wt%) and added slowly to the solution under vigorous agitation. EFFECT:The problems inevitable to organic solvents, e.g. hazards of fire and explosion, pollution of working, environment residual solvent in the coating layer, etc. can be solved.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing enteric coated drugs using solutions of enteric cellulose derivatives in an aqueous medium.

Conventionally, the method of manufacturing enteric-coated drugs has been considered to be, but in this case, a large amount of S-containing solvent is used, so there is a risk of fire, a single shot, and a poor working environment. ,
There are problems with residual solvent in the coated film, and further problems with recovery or processing equipment for organic cuttings, and it is also disadvantageous in terms of cost.

For this reason, it is desired to develop a technology for producing enteric coated drugs using the coating f&1, which does not use the organic solution side.For this purpose, a coating liquid made by suspending and dispersing a finely powdered coating base is being developed. Attempts have been made to use a coating solution made by emulsion polymerization of an acrylic monomer mixture, but in these cases, the suspension or emulsion may be destroyed and the spray nozzle may become clogged during the coating operation. Furthermore, acrylic-based rich polymers have the disadvantage that there is a concern that emulsifiers, unreacted monomers, etc. may remain.

The present invention was completed as a result of intensive research in view of the disadvantages of the conventional technology, and it involves dissolving an enteric-coated cellulose derivative in alkaline water, and then dissolving a carboxylic acid in an amount equal to or more than 50% of the equivalent amount of the alkali. The present invention relates to a method for producing an enteric coated drug, characterized in that a solid drug is coated with a solution obtained by adding .

The present invention will be explained in detail below.

The method of the present invention involves dissolving enteric-coated cellulose derivatives in alkaline water for 10 minutes, followed by addition of carboxylic acids.
The addition of carboxylic acid has the effect of increasing the water resistance of the coating to china clay. This is because the alkali salt of the water-soluble IIS cellulose derivative is liberated by the carboxylic acid, or the carboxylic acid remains in the coating.
This is thought to be because when it comes into contact with water, the water in or near the coating becomes acidic, making the coating insoluble.

11 As the enteric cellulose derivative used in the method of the present invention, any conventionally known enteric cellulose derivative may be used.

This includes monoesters of various cellulose ethers and polybasic acids, monoesters of monocarboxylic esters of cellulose or various cellulose ethers and polybasic acids, and carboxymethyl ethers of alkyl cellulose. Examples of the cellulose ethers include methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose,
Hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, etc. are used as cellulose or cellulose ether carboxylic acid esters such as acetic acid, flopionic acid, lactate esters of cellulose or the above-mentioned cellulose ethers, and polybasic acids include phthalic acid. , tetrahydrophthalic acid, hexahydrophthalic acid, 1. trimellitic acid, maleic acid.

Examples include conolic acid and the like.

Specific examples of such enteric cellulose derivatives include hydroxypropyl methylcellulose phthalate,
Hydroxypropylcellulose phthalate, cellulose acetate phthalate, cellulose acetate, hydroxypropylmethylcellulose acetate.

Examples include carboxymethylethylcellulose.

In the method of the present invention, the enteric cellulose derivative is first dissolved in alkaline water, but in this case it is not necessary to completely dissolve it, and even if undissolved suspended particles remain,
This is because fine particles will form a homogeneous film as they dry during the coating operation. The amount of alkali used in the alkaline water is usually an equivalent of 50% or more of the equivalent of the carboxyl group contained in the enteric-coated cellulose derivative, but if fine particles of the enteric-coated cellulose derivative are used, a smaller amount of alkali may be used. , or in excess of the equivalent amount of carboxyl group.

This is not preferred because a large amount of alkali g and - are required.

The types of alkalis used for alkaline water include lithium hydroxide, sodium hydroxide, alkali metal hydroxides such as saponified potassium, charcoal #II9thium, lithium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, and carbonic acid. Examples include alkali metal carbonates such as potassium hydrogen, ammonia, and the like. Note that polyvalent metal hydroxides or carbonates cannot be used because they make the coating material insoluble.

Next, carboxylic acid is added, the amount of which is at least 60% (1i1 or 60%) of the equivalent of the alkali added previously.
If the amount is less than this, the water resistance of the coating will be lost, and the coating will be destroyed before it reaches the stomach or inside the helmet, and the desired AM function will not be achieved. I can't demonstrate it.

The carboxylic acids used here include acetic acid, propionic acid, monocarboxylic acids such as benzoic acid, oxalic acid, cohelic acid, maleic acid, adipic acid, glutaric acid,
Examples include polycarboxylic acids such as phthalic acid, terephthalic acid, tetrahydrophthalic acid, and hexahydrophthalic acid, and these carunic acids are not limited to
One or more types may be used together. Note that if a mineral acid such as hydrochloric acid is used instead of carboxylic acid, hard particles will precipitate, which not only tends to clog the spray nozzle during the coating operation, but also deteriorates drabness, so it cannot be used.

When dissolving the enteric cellulose derivative, first disperse the enteric cellulose derivative in water in order to prevent particle agglomeration and dissolve it quickly.
Add the alkali or alkaline aqueous solution while stirring. Carboxylic acid is then added, but a large gel-like mass precipitates out.

To avoid clogging the spray nozzle, gradually add the acid diluted with water while stirring vigorously to avoid forming a gel-like mass to obtain a solution. The concentration of carboxylic acid that does not precipitate a gel-like substance varies depending on the enteric cellulose derivative and the type of carboxylic acid, but is usually SL% or less. 'The concentration of the enteric cellulose derivative in the solution used for coating is determined taking into account the ease of coating operation, etc., and is usually in the range of 3 to Is weight %. Below this lower limit, the coating operation takes a long time, and above the upper limit, the viscosity of the coating liquid becomes high and the coating operation becomes difficult.

In addition, various additives such as colorants, flavoring agents, plasticizers, fillers, antifoaming agents, surfactants, and thickeners may be added to the solution used for coating, or these additives may be added to the solution used for coating. In order to improve dispersibility, a water-soluble mfgliiJtt such as methyl alcohol, ethyl alcohol, isopropyl alcohol, or acetone may be blended.

The target enteric-coated drug can be obtained by coating solid drugs such as tablets, round granules, capsules, etc. with the above solution, and this coating operation can be carried out using conventional methods such as pan coating equipment, drum A method using a type coating device, a fluid coating device, etc. may be used, and a wax may be coated after the coating operation, thereby improving water resistance.

In addition, when a solid drug is coated according to the method of the present invention, the solid drug may be coated with a coating material such as human mixy methyl cellulose in advance, which prevents wear and tear due to impact. The present invention can also be easily applied to solid drugs.

Next, the reference examples and examples of the present invention were further dispersed in the medium, and while stirring, 10
A solution was prepared by adding % aqueous sodium hydroxide solution.

Next, take a portion of this liquid, add a predetermined amount of various carboxylic acid aqueous solutions while stirring, and cast from this liquid at a drying temperature of 40°C to create a film of about 0.1-Rhinoceros. Using a pharmacopoeia test granule disintegration test device, tap water, pharmacopoeia F14 at 37°C.
The time taken for the film to completely dissolve in Liquid 1@ and Pharmacopoeia II 2 was measured and the results were as shown in the table.

However, the abbreviations added in the table have the same meaning as the queen.

HP: Hydroxylepropyl methyl cellulose phthalate (Shin-Etsu Chemical Exhibition, average particle size 10μm) Number of substitutions per anhydroglucose unit Hydroxypropoxyl group 1.81 Methoxyl group
0.24 Phthaloyl group 0.64 A8: Hydroxypropyl methylcellulose acetate succinate C Average particle size 10 μm) Number of substitutions per anhydroglucose unit Hydroxypropoxyl group 1.87 Methoxyl group 0.24 1 Cetyl group 0.60 Ridinoyl group 0.2 Is A8f) 1301 used in the reference example is replaced with water 161! (1) Distributed using an 8V type agitator made by Shimabata Seisakusho,
While stirring, add 79 d of normal sodium hydroxide aqueous solution.
*After the addition, 1.8% adipic acid aqueous solution 270jF was gradually added, and triethyl citrate 137 was further gradually added to prepare a coating liquid.

A part of lactose 7011, 8011 parts of starch and LHP were added to 8TRRA-1 type manufactured by Fuji Sangyo as a coating device.
O (Shin-Etsu Chemical) 1! 1 per tablet, mainly consisting of 1 part Sl
5G Misaki's simulated lock 300? Prepare the tablet temperature to 35-40
The coating solution was sprayed at a rate of about 151 P/min while maintaining the temperature at 151 P/min until the area per tablet was 1yo,/y. Further, in a polishing pan, a mixture of carnauba wax (weight ratio: 6:4) was added to the tablets in an amount of 3.2 to 3.
% coating to obtain enteric coated tablets.

When this tablet was subjected to a disintegration test according to the Tsuruju Revised Japanese Pharmacopoeia, there was no change in the test with the first liquid 1+, and it disintegrated in 23 to 26 minutes in the test with the second liquid. , For patent - Nisshin-Etsu Chemical Co., Ltd. Procedural Amendments Showa fullj March 23, 2017 Haruki Shimada, Commissioner of the Patent Office 1. Indication of the case 1920 Patent Application No. 17100 2. Name of the invention Manufacturing method 3, relationship with each case to be amended Patent applicant name (1G@) Shin-Etsu Chemical Co., Ltd. 6, Supplement 11: Target (amended matters) "Methylcellulose" is corrected to "Hydroxypropylmethylcellulose".

that's all

Claims (1)

[Claims] 1. A solid Al111 is coated with a solution obtained by dissolving an enteric cellulose derivative in alkaline water and then adding a carboxylic acid equivalent to 50% or more of the equivalent of the alkali. Method for producing soluble coating drug